Cyclopenta[c]pyrrole derivatives

ABSTRACT

2,4,5,6-Tetrahydrocyclopenta[c]pyrrole-4-carboxamide and 4-thiocarboxamide derivatives useful as anti-secretory and anti-ulcer agents are prepared by hydrolysis or thiohydrolysis of the corresponding 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitriles or, in the case of the thiocarboxamides, by reaction of the 4-carboxamide with phosphorus pentasulfide.

RELATED APPLICATIONS

This is a division of our prior, copending application Ser. No. 772,003,filed Feb. 25, 1977 now U.S. Pat. No. 4,126,620, patented Nov. 21, 1978which in turn is a continuation-in-part of our prior, copendingapplication Ser. No. 703,949, filed July 9, 1976, now U.S. Pat. No.4,098,797, patented July 4, 1978, which in turn is a division of ourprior application Ser. No. 558,807, filed Mar. 18, 1975, now U.S. Pat.No. 4,008,250, patented Feb. 15, 1977, which in turn is acontinuation-in-part of our prior application Ser. No. 346,005, filedMar. 29, 1973, now U.S. Pat. No. 3,928,380, patented Dec. 23, 1975.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides andthiocarboxamides useful as anti-secretory and anti-ulcer agents.

(b) Description of the Prior Art

Although the 2,4,5,6-tetrahydrocyclopenta[c]pyrrole ring system is known(see for example Volz et al., Tetrahedron Letters 47, 4111-14 (1969) whodisclose 1,3-dimethyl- and1,2,3-trimethyl-4-oxo-2,4,5,6-tetrahydrocyclopenta[c]pyrrole and Bergeret al., J. Org. Chem. 35, 3122 (1970) who disclose1,3-dimethyl-4-oxo-2,4,5,6-tetrahydrocyclopenta[c]pyrrole), derivativesof such ring system having exocyclic functions, other than methyl groupsat the 1-, 2- and 3-positions, have not been previously known.Furthermore the aforementioned prior art species are prepared bylaborious multi-step synthetic methods and are not known to have anyutility except as laboratory curiosities.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention relates to certain1,3-di-R₆ -2-R₇ -4-R₃ -6-R₄ -6-R₅-2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides andthiocarboxamides where R₃, R₄, R₅, R₆ and R₇ are hydrogen, lower-alkylor other organic groups more specifically defined hereinafter, which areuseful as anti-secretory and anti-ulcer agents.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically, the invention relates to2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carboxamides and4-thiocarboxamides, which are useful as anti-secretory and anti-ulceragents and which have the Formula I: ##STR1## where X is O or S; R₁ ishydrogen, lower-alkyl, di-lower-alkylamino-lower-alkyl,morpholino-lower-alkyl, 1-pyrrolidyl-lower-alkyl or1-piperidyl-lower-alkyl; R₂ is hydrogen or lower-alkyl, or the group##STR2## can represent a 1-imidazolyl group; each of R₃, R₄ and R₅ ishydrogen or methyl; each R₆ group is the same or different hydrogen,formyl (CHO) and lower-alkane-1,3-diol ketals thereof,phenyl-lower-alkyl, carboxy, carbo-lower-alkoxy,carbo-lower-alkoxy-lower-alkyl, carbo-lower-alkoxy-lower-alkenyl,carboxy-lower-alkyl, carboxy-lower-alkenyl, methyl, lower-alkenyl or agroup of the formula: ##STR3## where R₈ is hydrogen, lower-alkyl,lower-alkenyl, lower-alkynyl, phenyl or phenyl-lower-alkyl; R₉ ishydrogen, cyano (CN), lower-alkyl, lower-alkenyl, lower-alkynyl, phenyl,phenyl-lower-alkyl, carboxy, carbo-lower-alkoxy, carbamyl (CONH₂),aminomethyl (CH₂ NH₂), lower-alkanoyl, trichloromethyl,carbo-lower-alkoxy-lower-alkyl or carbo-lower-alkoxy-lower-alkynyl; R₁₀is hydrogen, benzoyl, lower-alkanoyl, carboxy-lower-alkanoyl (andammonium salts thereof) or lower-alkyl, R₁₀ being other than hydrogenonly when either one or both of R₈ and R₉ are hydrogen and R₉ beingcyano only when R₁₀ is hydrogen; and R₇ is hydrogen, lower-alkyl,halo-lower-alkyl, lower-alkenyl, lower-alkynyl,di-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl,1-pyrrolidyl-lower-alkyl, 1-piperidyl-lower-alkyl,carbo-lower-alkoxy-lower-alkyl, carboxy-lower-alkyl,carboxamido-lower-alkyl, thiocarboxamido-lower-alkyl,lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl,lower-alkyl-thio-lower-alkyl, cycloalkyl, cycloalkyl-lower-alkyl, 2-, 3-or 4-pyridyl, phenyl, phenyl-lower-alkyl, thienyl, 9-acridinyl,4-(2,1,3-benzothiadiazolyl), 2-benzothiazolyl, 3-carbazolyl,2-benzoxazolyl, 2- or 6-purinyl, 2-pyrazinyl, 4-pyrimidinyl,2-thiazolyl, 3-pyrazolyl, 2- or 6-pyrimidinyl, 2-benzimidazolyl,2-benzothiazolyl, 5-, 6- or 7-indazolyl, 5-isoquinolinyl, 3-pyridazinyl,2-thiadiazolyl, 5-tetrazolyl, 2-thiazolinyl, 3-(1,2,4-triazinyl),3-(1,2,4-triazolyl), or divalent-lower-alkylene having its valences ondifferent carbon atoms and joining two of the2,4,5,6-tetrahydrocyclopenta[c]pyrrole moieties together, and whereinthe phenyl, benzoyl and phenyl-lower-alkyl groups can be furthersubstituted in the phenyl nucleus by a single methylenedioxy orlower-alkyl group or by from one to three, the same or different,members of the group consisting of lower-alkyl, halogen (includingfluorine, bromine and chlorine), hydroxy, trifluoromethyl,lower-alkanoylamino, amino, di-lower-alkylamino,di-lower-alkyl-aminomethyl, carboxy, carboxamido, carbo-lower-alkoxy,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, nitro andsulfamoyl, except that both R₆ groups are not simultaneously hydrogenand further except that when R₇ is unsubstituted phenyl and R₆ at the3-position and R₈ are both hydrogen, R₉ is not unsubstituted-phenyl. Thetwo species defined by the latter excepting clauses have been found tobe inactive in one or both of the anti-secretory and anti-ulcer tests ashas also a species where R₇ is di-lower-alkoxy-substituted-phenyl.

Preferred compounds within the ambit of Formula I are those where X isO, each of R₁ and R₂ is hydrogen or lower-alkyl; each of R₃, R₄ and R₅is methyl; both R₆ groups are lower-alkyl; and R₇ is lower-alkyl orphenyl and also the compounds of formula I where X is O; R₁ and R₂ areeach hydrogen; R₃, R₄ and R₅ are each methyl; one R₆ is hydrogen,lower-alkyl or hydroxymethyl and the other is hydrogen, lower-alkyl orthe group: ##STR4## where R₈ is hydrogen, lower-alkyl, lower-alkenyl, orlower-alkynyl; and R₇ is phenyl (or substituted-phenyl), both of whichpreferred groups are represented by the formula: ##STR5## except thatboth R₆ groups are not simultaneously hydrogen.

As used herein the terms "lower-alkyl" and "lower-alkoxy" meansaturated, monovalent, aliphatic radicals, including straight orbranched-chain radicals, of from one to four carbon atoms as illustratedby, but not limited to, methyl, ethyl, propyl, isopropyl, butyl,sec.-butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, and the like.

As used herein the term "cycloalkyl" means saturated carbocyclic groupscontaining from three to six ring carbon atoms and having a total offive to ten carbon atoms, as illustrated by, but not limited to,cyclopropyl, cyclobutyl, 2-methylcyclobutyl and cyclohexyl.

As used herein the terms "lower-alkenyl" and "lower-alkynyl" meanmonovalent, aliphatic radicals of from three to six carbon atoms whichcontain at least one double or triple bond, and are either straight orbranched-chain as illustrated by, but not limited to, 1-(2-propenyl),1-(1-propenyl), 1-(3-methyl-2-propenyl), 1-(1,3-dimethyl-2-propenyl),1-(2-hexenyl), 1-(2-propynyl) and 1-(2-butynyl).

As used herein, the term "lower-alkylene" means divalent, aliphaticradicals, including straight or branched-chain radicals, of from one toeight carbon atoms, and having its valences on different carbon atoms asillustrated by, but not limited to, methylene, 1,2-ethylene,1,4-butylene, 1,6-hexylene, 3-methyl-1,5-pentylene and 1,8-octylene.

As used herein, the terms "lower-alkenylene" and "lower-alkynylene" meandivalent, aliphatic radicals of from two to six carbon atoms whichcontain at least one double or triple bond and can be straight orbranched, as illustrated by, but not limited to, 1,2-ethenyl,1,2-ethynyl, 1,4-(2-butenyl), 1,4-(2-butynyl), 1,6-(2-hexenyl) and1,6-(2-hexynyl).

The compounds of Formula I where X is O; R₁ and R₂ are each hydrogen;and R₃, R₄, R₅, R₆ and R₇ have the meanings given above are prepared byhydrolysis, under acid, basic or neutral conditions, of thecorresponding 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrileshaving the Formula II: ##STR6## where R₃, R₄, R₅ and R₆ have themeanings given above, and R₇, in addition to the various meanings givenabove, represents cyano-lower-alkyl. Hydrolysis under basic conditionsis advantageously effected by warming a solution of the nitrile ofFormula II in an inert organic solvent, for example methanol, ethanol orisopropanol, containing a molar excess of an alkali metal hydroxide.Hydrolysis in a neutral medium is advantageously carried out using theprocedure of Bennett et al., J. Am. Chem. Soc. 95, 3030-1 (1973) inwhich a planar, nonionic tertiary phosphine metal-hydroxy complex isused as a catalyst. Hydrolysis in an acid medium is carried out byheating a solution of the nitrile in a mineral acid, for example,phosphoric acid, polyphosphoric acid or aqueous sulfuric acid at atemperature from 0° C. to around 70° C. During the reaction, the nitrilegroup in the compounds of Formula II where R₇ is cyano-lower-alkyl ishydrolyzed simultaneously with the nitrile group attached to the4-position of the 2,4,5,6-tetrahydrocyclopenta[c]pyrrole to thus producecompounds of Formula I where R₇ is carboxamido-lower-alkyl, and theabove-described procedure constitutes a preferred method of preparingthe latter compounds.

The compounds of Formula I where X is S; R₁ and R₂ are each hydrogen;and R₃, R₄, R₅, R₆ and R₇ have the meanings given above are preferablyprepared by thiohydrolysis of the nitriles of Formula II using theprocedure of Karrer et al., Helv. Chim. Acta 28, 820 (1945) whichinvolves reacting the nitrile with a saturated solution of ammonia andhydrogen sulfide in an organic solvent, preferably a lower-alkanol, atroom temperature. Alternatively, the reaction can be carried out underpressure in an autoclave at a temperature from 150°-160° C. using theprocedure described by Ralston et al. J. Org. Chem. 4, 68 (1939). As inthe case of the hydrolysis of the compounds of Formula II to those ofFormula I where X is O, thiohydrolysis of the compounds of Formula IIwhere R₇ is cyano-lower-alkyl affords the compounds of Formula I whereR₇ is thiocarboxamido-lower-alkyl, and the above-described procedureconstitutes a preferred method of preparing the latter compounds.

Alternatively, and preferably, the compounds of Formula I where X is Sare prepared by reaction of the corresponding compounds where X is Owith phosphorus pentasulfide. The reaction is carried out by heating thereactants directly either with or without a solvent. Preferred solvents,when used, are benzene, toluene, xylene, dioxane and the like.

The compounds of Formula I where R₇ is other than hydrogen can also beprepared by reaction of the corresponding compounds where R₇ is hydrogenwith a strong base, for example alkali metal hydrides or alkali metalamides, in an inert organic solvent, for example dimethylsulfoxide,dioxane, dimethylformamide, tetrahydrofuran, dibutyl ether, and thelike, and reaction of the resulting salt with an appropriate alkylatingagent, R₇ X, where X is the anion of a strong mineral acid, for examplea hydrogen halide or sulfuric acid, and R₇ X, where X is the anion of astrong mineral acid, for example a hydrogen halide or sulfuric acid, andR₇ has the meanings given above. The reaction is preferably carried outat low temperatures, i.e. from 0° C. to about 40° C. During thereaction, alkylation can take place at either the amide nitrogen atom,when compounds where R₁ and R₂ are both hydrogen are used as startingmaterials, or at the pyrrole nitrogen atom, and it is possible toisolate both isomeric products from the reaction mixture.

The compounds of Formula I where R₇ is lower-alkenyl are preferablyprepared by Hofmann elimination of a tertiary amine from a compound ofFormula I where R₇ is di-lower-alkylamino-lower-alkyl,morpholino-lower-alkyl, 1-pyrrolidyl-lower-alkyl or1-piperidyl-lower-alkyl. The method comprises converting the tertiaryamine to a quaternary ammonium salt by reaction of the amine with anester of a strong inorganic acid, e.g. a lower-alkyl halide or adi-lower-alkyl sulfate, and reacting the quaternary salt with silveroxide, preferably in an aqueous medium to effect conversion of thequaternary salt to the corresponding ammonium hydroxide, whichspontaneously decomposes in an aqueous medium at ambient temperature tothe N-lower-alkenyl-substituted compound of Formula I and a tertiaryamine. It is preferred to use a dimethylamino-lower-alkyl substitutedcompound of Formula I as starting material and a methyl halide ordimethyl sulfate as quaternizing agent.

The compounds of Formula I where R₁ and/or R₂ are other than hydrogenand R₇ is other than hydrogen are prepared by reacting the correspondingcarboxamides where either one or both of R₁ and R₂ are hydrogen with astrong base, for example an alkali metal hydride or an alkali metalamide, followed by reaction of the resulting salt with an alkylatingagent, for example a lower-alkyl halide or a di-lower-alkyl sulfate. Asindicated above, when compounds where both R₁ and R₂ are hydrogen areused as starting materials, alkylation can take place on both the ringand amide nitrogen atoms, necessitating separation of the isomericproducts. Preparation of the compounds where both R₁ and R₂ arelower-alkyl is best effected by stepwise alkylation of the carboxamide,that is alkylation of the compounds where both R₁ and R₂ are hydrogenusing one mole of a strong base and one mole of an alkylating agentfollowed by a second alkylation of the resultingN-lower-alkylcarboxamide where one of R₁ and R₂ is lower-alkyl. Thereaction with a second mole of strong base takes place under much morevigorous conditions involving use of higher reaction temperatures, i.e.from about 50° C. to about 150° C., and longer reaction times than theabove-described method for alkylation at the pyrrole nitrogen atom ormonoalkylation at the amide nitrogen atom, which take place at lowertemperatures and shorter reaction times. The reaction is carried out inan inert organic solvent, for example dimethylsulfoxide, dioxane,dimethylformamide, tetra-hydrofuran, dibutyl ether, and the like.

The compounds of Formula I where one or both R₆ groups are hydroxymethyl(R₈, R₉, and R₁₀ are hydrogen), are prepared by reduction, with analkali metal borohydride, of the corresponding compounds of Formula Iwhere one or both R₆ groups are formyl. The reaction is carried out inan inert organic solvent, for example lower-alkanols, dioxane, diethylether, and the like. The reaction generally takes place at ambienttemperature, although elevated temperatures up to the boiling point ofthe solvent can be used to expedite the reaction. The method for thepreparation of compounds where both R₆ groups are hydroxymethyl isrepresented by the equation: ##STR7## where R₁, R₂, R₃, R₄, R₅, R₇, andX have the meanings given above.

The compounds of Formula I where one or both R₆ moieties is the group##STR8## where R₈ is hydrogen and R₉ is lower-alkyl, lower-alkynyl,lower-alkenyl, phenyl, phenyl-lower-alkyl, trichloromethyl,carbo-lower-alkoxy-lower-alkylene or carbo-lower-alkoxy-lower-alkynyleneare prepared by reaction of the corresponding compound where one or bothR₆ groups is formyl with an organo metallic compound such as an organolithium, e.g. a lower-alkyl, lower-alkenyl, lower-alkynyl or phenyllithium, or an organo magnesium halide, e.g. phenyl (orsubstituted-phenyl) magnesium halide or a phenyl-lower-alkyl magnesiumhalide, and hydrolysis of the resulting organometallic compound. Thereaction is carried out in an inert organic solvent such astetrahydrofuran or diethyl ether.

The compounds of Formula I where one or both R₆ groups is lower-alkenylare prepared by heating the corresponding carbinol where R₈ is hydrogenand R₉ is lower-alkyl in an organic solvent, for example benzene,toluene or xylene. In some cases recrystallization of the carbinols fromsuch boiling solvents is sufficient to effect dehydration.

The compounds of Formula I where R₈ is lower-alkyl, lower-alkynyl,lower-alkenyl, phenyl or phenyl-lower-alkyl and R₉ is the same ordifferent lower-alkyl, lower-alkynyl, lower-alkenyl, phenyl orphenyl-lower-alkyl are prepared by reacting the corresponding compoundswhere R₆ is carbo-lower-alkoxy with either four molar equivalents of anorgano metallic compound as indicated above, which affords compoundswhere R₈ and R₉ are identical, or if desired only two moles of theorgano metallic compound can be used which affords compounds where R₆ isa ketone group, i.e. R₈ --CO (or R₉ --CO). The latter is then reactedwith two moles of a different organo metallic compound to give thecarbinols where R₈ and R₉ are different. In each of the above-describedreactions requiring use of an organo metallic compound, one mole of theorgano metallic reagent in addition to that required for reaction at the1- or 3-positions is required when the compounds of Formula I where oneor both of R₁ and R₂ is hydrogen is used as the starting material,because one mole of the organo metallic reagent reacts with one of theprotons on the amide nitrogen.

The compounds of Formula I where R₉ is cyano, carbamyl or aminomethylare prepared via the cyanohydrin (i.e. R₉ is cyano) of the correspondingcompounds where R₆ is formyl. The cyanohydrins are prepared by reactionof the formyl compounds with diethyl aluminum cyanide in an inertorganic solvent, for example benzene, toluene, xylene, tetrahydrofuran,dioxane or mixtures of these solvents. A preferred solvent is a mixtureof benzene and tetrahydrofuran. The cyanohydrins in turn, on eitherhydrolysis with dilute sulfuric acid using the same conditions asdescribed for hydrolysis of the compounds of Formula II to Formula I, orcatalytic reduction with hydrogen over platinum oxide afford,respectively, the compounds where R₉ is carbamyl and aminomethyl.

The compounds of Formula I where R₉ is carboxy or carbo-lower-alkoxy areprepared by hydrolysis of the corresponding compounds where R₉ istrichloromethyl, using the procedure described below for preparing thecompounds where R₆ is formyl or carboxy, to afford the compounds whereR₉ is carboxy. The esters are prepared from the acids by standardesterification procedures.

The compounds of Formula I where R₉ is lower-alkanoyl are prepared byhydroxylation of the corresponding compounds where R₉ is lower-alkynylusing dilute sulfuric acid.

The compounds of Formula I where R₁₀ is lower-alkyl are prepared byreacting the free carbinols (R₁₀ is hydrogen) with a lower-alkanol inthe presence of a mineral acid. The compounds where R₁₀ is an estergroup, i.e. benzoyl, lower-alkanoyl or carboxy-lower-alkanoyl areprepared by reacting the carbinol either with an acid halide or an acidanhydride in the presence of an acid acceptor, for example pyridine or atri-lower-alkylamine.

The compounds of Formula I where one or both R₆ groups are carboxy areprepared by oxidizing the corresponding compounds where one or both R₆groups are formyl with one mole of an oxidizing agent per formyl group,for example alkaline permanganate. When it is desired to preparecompounds of Formula I where one R₆ group is formyl and the other iscarboxy, then compounds where both R₆ groups are formyl are used, andone of the two formyl groups must be individually protected while othertransformations are carried out on the other formyl group after whichthe protecting group is removed to regenerate the formyl group which canthen either be preserved in the final products or if desired utilized asa handle for conversion to other groups such as various carbinols asdescribed above. A particularly effective means of protecting one or twoformyl groups is to convert the latter to a ketal by reaction of theformyl derivative with one molar equivalent of an alkanediol (or withtwo molar equivalents of a lower-alkanol) in an anhydrous medium and inthe presence of a strong acid. Preferred alkanediols are1,3-propanediols which may be straight or branched, for example,2,2-dimethyl-propanediol or 1,1,3-trimethyl-1,3-propanediol (i.e.2-methylpentane-2,4-diol). The resulting mixture of products containinga ketal group at each of the 1- and 3-positions can, if desired, beseparated into the individual components, and each component treatedseparately in subsequent synthetic steps. The unprotected formyl groupcan then, for example, be oxidized to the carboxylic acid using analkaline medium in which the ketal group is stable, for example alkalinepermanganate. The carboxyl group thus produced can either be retained assuch or converted to an ester moiety or, if desired, it can be removedby heating the product at a temperature of around 200°-250° C. in a highboiling organic solvent, for example dimethylaniline, ethylene glycol orpropylene glycol.

The corresponding compounds of Formula I where one R₆ group is formyland the other a carboxy group can also be prepared by reaction of thecorresponding compound of Formula I where both R₆ groups are methyl withfive molar equivalents of sulfuryl chloride, which affords the compoundswhere one R₆ group is dichloromethyl and the other trichloromethyl, andhydrolysis of the latter with water in a water-miscible organic solventas described above. The compounds where one or both R₆ groups arecarbo-lower-alkoxy are prepared from compounds wherein one or both R₆groups are carboxy by standard esterification procedures comprisingreacting the carboxylic acid with a lower-alkanol.

The compounds of Formula I where R₁ and R₂ are each hydrogen can also beprepared by reduction with one molar equivalent of diisobutyl aluminumhydride (DIBAL) of the compounds of Formula II, and oxidation withoxygen of the resulting cyclopenta[c]pyrrole-4-aldimide having theFormula III without isolation of the latter. The method is illustratedby the following reaction sequence: ##STR9## where R₃, R₄, R₅, R₆ and R₇have the meanings given above.

The compounds of Formula III can also be converted to the final productsof Formula I where R₁ and R₂ are hydrogen and X is O by reacting thealdimide of Formula III with a peracid, e.g. performic, peracetic orperbenzoic acid, to produce an oxaziridine having the Formula IV, whichon thermal or photochemical decomposition by irradiation with lightaffords the compounds of Formula I. The method is represented by thereaction sequence: ##STR10## where R₃, R₄, R₅, R₆ and R₇ have themeanings given above.

Still another method for converting the carbonitriles of Formula II tothe carboxamides of Formula I where R₁ and R₂ are hydrogen and X is Ocomprises oxidizing the carbonitrile with peroxide, e.g. hydrogenperoxide, in a basic medium, e.g. in the presence of an alkali metalhydroxide, and decomposition of the resulting perimidate of Formula V byheating the reaction medium. A preferred solvent is acetone. The methodis represented by the reaction sequence: ##STR11## where R₃, R₄, R₅, R₆and R₇ have the meanings given above.

The intermediate 2,4,5,6-tetrahydrocyclopenta[c]pyrrole-4-carbonitrilesof Formula II are prepared by a variety of different methods dependingupon the identities of the various R₃, R₄, R₅, R₆ and R₇ groups. Thesemethods are described in detail in U.S. Pat. No. 4,008,250, patentedFeb. 15, 1977 on application Ser. No. 558,807 identified above as a"RELATED APPLICATION", the disclosure of which is incorporated herein byreference.

The novel compounds of the instant invention are the compounds ofFormula I and includes the acid-addition salts of the compounds whichcontain a basic, salt-forming group such asdi-lower-alkylamino-lower-alkyl, morpholino-lower-alkyl,1-pyrrolidyl-lower-alkyl, 1-piperidyl-lower-alkyl, aminomethyl,di-lower-alkylaminomethyl or a basic heterocyclic group such as pyridyl.The compounds of Formula I in free base form are converted to theacid-addition salt form by interaction of the base with an acid in anorganic solvent and isolating the salt directly or by concentration ofthe solution. In like manner, the free base can be regenerated from theacid-addition salt form in the conventional manner, that is by treatingthe salts with cold, weak aqueous bases, for example alkali metalcarbonates and alkali metal bicarbonates. The bases thus regenerated canthen be interacted with the same or a different acid to give back thesame or a different acid-addition salt. Thus the original bases and allof their acid-addition salts are readily interconvertible.

In standard biological test procedures, described generally by Shay etal., Gastroenterology 5, 43 (1945) and 26, 906 (1954), the compounds ofFormula I have been found to possess anti-secretory and anti-ulceractivity and are thus useful as anti-secretory and anti-ulcer agents.The anti-secretory and anti-ulcer test procedures used are fullydescribed in our U.S. Pat. No. 4,008,250.

The compounds of Formula I were thus found to inhibit secretion ofgastric fluids and to inhibit reserpine-induced stomach ulceration whenadministered in a dose range of from around 10 mg./kg. to around 200mg./kg. The compounds are preferably administered orally, and the amountof a particular compound to be administered, either alone or as theessential active ingredient in a formulation, will range from about 10to about 200 mg./kg.

The actual determination of the numerical biological data definitive fora particular compound of Formula I is readily determined by standardtest procedures by technicians versed in pharmacological test procedureswithout the need for any extensive experimentation.

The compounds of Formula I can be prepared for use by incorporation inunit dosage form as tablets or capsules for oral administration eitheralone or in combination with suitable adjuvants such as calciumcarbonate, starch, lactose, sodium bicarbonate, sodium lauryl sulfate,sugar, dextrose, mannitol, cellulose, gum acacia, and the like.Alternatively, they can be formulated for oral administration in aqueousalcohol, glycol, or oil solutions or oil-water emulsions in the samemanner as conventional medicinal substances are prepared. They can alsobe formulated for oral use with foodstuffs or admixed with foodstuffsfor veterinary use.

The molecular structures of the compounds of the invention were assignedon the basis of study of their infrared, ultraviolet, and NMR spectra,and confirmed by the correspondence between calculated and found valuesfor elementary analyses for the elements.

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points are uncorrected.

EXAMPLE 1

A mixture of 22 g. (0.10 mole) of2,4,5,6-tetrahydro-1,2,3,4,6,6-hexamethylcyclopenta[c]pyrrole-4-carbonitrilein 10 ml. of water and 100 ml. of concentrated sulfuric acid was warmedto 85° C. on a steam bath and heated with stirring for about fiveminutes. The resulting dark brown solution was poured into water,basified with 35% aqueous sodium hydroxide until no further solidseparated, and the solid which precipitated was collected, washed withwater, air dried, and recrystallized with charcoaling from ethyl acetateto give 17.3 g. of2,4,5,6-tetrahydro-1,2,3,4,6,6-hexamethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 184.5°-187.5° C.

Following a procedure similar to that described in Example 1, using anappropriate2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile ofFormula II, the following2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta-[c]pyrrole-4-carboxamidesof Formula I were prepared, where in each instance, R₁ and R₂ are eachhydrogen; X is 0; R₃, R₄ and R₅ are each CH₃ ; and where, unless notedotherwise by the notations "(1)" and "(3)" to indicate R₆ substituentsin the 1- and 3-positions, respectively, both R₆ groups have themeanings indicated in the column headed "R₆ ".

                                      Table 1a                                    __________________________________________________________________________    Example                                                                            R.sub.6    R.sub.7     Wt. II                                                                             Wt. I                                                                             m.p. (°C.)/Solvent                __________________________________________________________________________    1A   CH.sub.3   H           60   28  230-233/ethyl acetate                    1B   CH.sub.3   CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                              29.3 19  114.5-116/acetonitrile                   1C   CH.sub.3   --(CH.sub.2).sub.6 --                                                                     45   10.5                                                                              218-221/DMF                              1D   CH.sub.3   CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                         56   17.8                                                                              115.5-117.5/cyclo-                                                            hexane                                   1E   CH.sub.3   4-NH.sub.2 SO.sub.2 C.sub.6 H.sub.4                                                       44   1.8 258-260/methanol                         1F   CH.sub.3   C.sub.6 H.sub.5                                                                           28   18  132-135/cyclohexane                      1G   CH.sub.3   C.sub.2 H.sub.5                                                                           37.2 15.2                                                                              162-164/ethyl acetate                    1H   CH.sub.3   C.sub.3 H.sub.7                                                                           40   34.4                                                                              164.5-166.5/isopro-                                                           panol                                    1J   CH.sub.3   CH.sub.2 C.sub.6 H.sub.5                                                                  24   20.2                                                                              170-171/ethyl                                                                 acetate                                  1K   CH.sub.3   4-CH.sub.3 OC.sub.6 H.sub.4                                                               70   37  198.5-201/isopro-                                                             panol                                    1L   CH.sub.3   4-CH.sub.3 C.sub.6 H.sub.4                                                                58.4 32  198-202/acetonitrile                     1M   CH.sub.3   4-ClC.sub.6 H.sub.4                                                                       62.5 34  16.5-167.5/aceto-                                                             nitrile                                  1N   CH.sub.3   3-ClC.sub.6 H.sub.4                                                                       81.4 60  139-142/acetonitrile                     1P   CH.sub.3   2-pyridyl   86   32  187-189/acetonitrile                     1Q   CH.sub.3   3-CH.sub.3 C.sub.6 H.sub.4                                                                60   27.4                                                                              149.5-151.5/methanol                     1R   CH.sub.3   2-ClC.sub.6 H.sub.4                                                                       116  14.7                                                                              181-183/methanol                         1S   CH.sub.3   2-CH.sub.3 C.sub.6 H.sub.4                                                                100  28  159-161/methanol                         1T   CH.sub.3   4-FC.sub.6 H.sub.4                                                                        88   54  150-151/isopropanol                      1U   CH.sub.3   4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                       64.2 31.5                                                                              238-241/DMF                              1V   CH.sub.3   4-HOC.sub.6 H.sub.4                                                                       88.2 31.7                                                                              249-251/methanol                         1W   CH.sub.3   4-CH.sub.3 CONHC.sub.6 H.sub.4                                                            55   22  236-239/methanol                         1X   CH.sub.3   CH.sub.2 CH.sub.2 CONH.sub.2                                                              23.9 4.3 130.5-133/acetone                        1Y   CH.sub.3   C.sub.4 H.sub.9                                                                           30.7 7.8 135-137/cyclohexane                      1Z   CH.sub.3   iso-C.sub.3 H.sub.7                                                                       25.6 13.5                                                                              156-158/cyclohexane                      1AA  CH.sub.3   CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                        103.1                                                                              21.5                                                                              109-111/hexane                           1AB  CHO        C.sub.6 H.sub.5                                                                           10   3.4 164.5-166.5/methanol                     1AC  CH.sub.3   CH.sub.2 COOC.sub.2 H.sub.5                                                               55   33.5                                                                              138-140/ether-                                                                ethanol                                  1AD  CH.sub.3   cyclohexyl  81   31  125-150/isopropanol                      1AE  CH.sub.3   cyclopropyl 12.1 10.1                                                                              188-192                                  1AF  CH.sub.3   cyclopentyl 6.9  4.6 152-155/cyclohexane                      1AG  CH.sub.3   CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                       1.9  0.5 110-113/heptane-                                                              hexane                                   1AH  CH.sub.3   CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O                                            9.8  8.6 142-144/hexane                           1AJ  CH.sub.3   CH.sub.2 CH.sub.2 CH.sub.2 OH                                                             2.6                                               1AK  CH.sub.3   cyclobutyl  9.3  5.5 149-152                                  1AL  CH.sub.3   cyclopropyl-CH.sub.2                                                                      25   10.9                                                                              150-153/ethanol-H.sub.2 O                1AM  CH.sub.3   sec-C.sub.4 H.sub.9                                                                       40   29.3                                                                              152-154/cyclohexane                      1AN  CH.sub.3   iso-C.sub.4 H.sub.9                                                                       18.5 12.0                                                                              148.5-151/hexane                         1AP  CH.sub.3   3,4-(HO).sub.2 C.sub.6 H.sub.3                                                            5.0.sup.(a)                                                                        2.3 129-131/ethyl acetate-                                                        pentane                                  1AQ  CH.sub.3   4-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                        45   8   212-214/ethanol-H.sub.2 O                1AR  CH.sub.3   3-CF.sub.3 C.sub.6 H.sub.4                                                                6.3  4.0 150-153/benzene-                                                              pentane                                  1AS  CH.sub.3   CH.sub.2 C.tbd.CH                                                                         22.6 14.7                                                                              141-145/cyclohexane                      1AT  CH.sub.3   CH.sub.2 CH.sub.2 F                                                                       17.7 11.1                                                                              130-131/benzene-                                                              hexane                                   1AU  CH.sub. 3  CH.sub.2 CH.sub.2 Cl                                                                      20.0 17.3                                                                              145.5-147/benzene-                                                            hexane                                   1AV  CHO(1)     C.sub.6 H.sub.5                                                                           6.3  4.2 190-192/isopropanol                           H(3)                                                                     1AW  CHO(1)     C.sub.6 H.sub.5                                                                           29.8 1.0 123-126/benzene                               CH.sub.3 (3)                                                             1AX  CHO(1)     4-FC.sub.6 H.sub.4                                                                        6.1  1.0 241 (dec.)/methanol                           COOH(3)                                                                  1AY  CHO(1)     C.sub.6 H.sub.5                                                                           14.0 7.9 231-232/acetone                               COOH(3)                                                                  1AZ  CHO(1)     4-FC.sub.6 H.sub.4                                                                        5.0  3.7 193-196/isopropanol                           H(3)                                                                     1BA  CH.sub.3 (1)                                                                             C.sub.6 H.sub.5                                                                           3.0  3.1 121.5-123.5/ether-                            COOCH(3)                        hexane                                   1BB  COOCH.sub.3 (1)                                                                          C.sub.6 H.sub.5                                                                           6.0  5.09                                                                              195-196.5/ether-                              H(3)                            hexane                                   1BC  CH.sub.3 (1)                                                                             C.sub.6 H.sub.5                                                                           3.0  2.7 110-112/heptane                               CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5 (3)                                 1BD  CH.sub.3 (1)                                                                             C.sub.6 H.sub.5                                                                           4.0  1.3 172-174/hexane                                CH═CHCOOC.sub.2 H.sub.5 (3)                                          1BE  CH═CHCOOC.sub.2 H.sub.5 (1)                                                          C.sub.6 H.sub.5                                                                           4.5  1.3 197-198.sup.(b)                               H(3)                                                                     1BF  CH═ CHCOOH(1)                                                                        C.sub.6 H.sub.5                                                                           4.5  1.4 210-212.sup.(b)                               H(3)                                                                     1BG  CH.sub.3   2-pyrazinyl 1.0  1.1 169-171/acetonitrile                     1BH  CH.sub.3   4-pyridyl   3.5  3.1 118.5-120/acetonitrile                   1BJ  CHO(1)     H           15.0 4.0 117-119/heptane                               H(3)                                                                     1BK  CH.sub.3   4-C.sub.6 H.sub.4 COOC.sub.2 H.sub.5                                                      35   12.8                                                                              188-191/benzene-                                                              hexane                                   1BL  CH.sub.3   3-HOC.sub.6 H.sub.4                                                                       10   1.5 216-218/ethyl acetate                    1BM  CH.sub.3   3-(CH.sub.3).sub.2 N-4-HOC.sub.6 H.sub.3                                                  2.0  1.9 110-112/benzene.sup.(c)                  1BN  CH.sub.3   3-HOC.sub.6 H.sub.3 -4-COOC.sub.2 H.sub.5                                                 11.0 8.4 170-172/benzene-hexane                   1BP  CH.sub.3   4-HOC.sub.6 H.sub.3 -3-COOC.sub.2 H.sub.5                                                 9.0  3.3 172-174/ethanol                          __________________________________________________________________________     .sup.(a) Starting material was 1[3,4(2,2-propylenedioxy)phenyl] compound.     .sup.(b) The products of Examples 1BE and 1BF were obtained as a mixture      from the same starting material and were separated by partitioning betwee     ethyl ether and ammonium hydroxide and each product isolated without          recrystallization.                                                            .sup.(c) Contains one mole of benzene as solvate.                        

It is contemplated that by following a procedure similar to thatdescribed in Example 1, using an appropriate2,4,5,6-tetrahydro-cyclopenta[c]pyrrole-4-carbonitrile of Formula II inrefluxing 90% aqueous sulfuric acid, the following compounds of FormulaI can be prepared where, in each instance, R₁ and R₂ are hydrogen; and Xis 0.

                  Table 1b                                                        ______________________________________                                        Example                                                                              R.sub.3                                                                              R.sub.4 R.sub.5                                                                            R.sub.6                                                                              R.sub.7                                     ______________________________________                                        1BQ    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             4-BrC.sub.6 H.sub.4                         1BR    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2,4,6-Cl.sub.3 C.sub.6 H.sub.2              1BS    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-Cl-4-CH.sub.3 C.sub.6 H.sub.3             1BT    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                              ##STR12##                                  1BU    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             4-CF.sub.3 C.sub.6 H.sub.4                  1BV    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2,4,6-(CH.sub.3).sub.3 C.sub.6 H.sub.2      1BW    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             CH.sub.2 CH.sub.2 SC.sub.2 H.sub.5          1BX    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           C.sub.3 H.sub.7                                                                      C.sub.6 H.sub.5                             1BY    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           iso-C.sub.3 H.sub.7                                                                  C.sub.6 H.sub.5                             1BZ    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           C.sub.4 H.sub.9                                                                      C.sub.6 H.sub.5                             1CA    CH.sub.3                                                                             H       H    CH.sub.3                                                                             C.sub.6 H.sub.5                             1CB    CH.sub.3                                                                             H       H    CH.sub.3                                                                             CH.sub.3                                    1CC    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             4-NH.sub.2 C.sub.6 H.sub.4                  1CD    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             cyclohexyl-CH.sub.2                         1CE    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             CH.sub.2 CH.sub.2 N(CH.sub.2).sub.4         1CF    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             CH.sub.2 CH.sub.2 N(CH.sub.2).sub.5         1CG    H      H       H    CH.sub.3                                                                             CH.sub.3                                    1CH    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-thienyl                                   1CJ    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             3-H.sub.2 NCOC.sub.6 H.sub.4                1CK    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             3-CH.sub.3 SC.sub.6 H.sub.4                 1CL    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             4-O.sub.2 NC.sub.6 H.sub.4                  1CM    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           C.sub.6 H.sub.5 CH.sub.2                                                             C.sub.6 H.sub.5                             1CN    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             3-pyridyl                                   1CP    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             9-acridinyl                                 1CQ    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             4-(2,1,3-benzo-                                                               thiazolyl)                                  1CR    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-benzothiazolyl                            1CS    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub. 3                                                                            3-carbazolyl                                1CT    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-benzoxazolyl                              1CU    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-purinyl                                   1CV    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             6-purinyl                                   1CW    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             4-pyrimidinyl                               1CX    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-thiazolyl                                 1CY    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             3-pyrazolyl                                 1CZ    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-pyrimidinyl                               1DA    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             6-pyrimidinyl                               1DB    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-benzimidazolyl                            1DC    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-benzothiazolyl                            1DD    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             5-indazolyl                                 1DE    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             6-indazolyl                                 1DF    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             7-indazolyl                                 1DG    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             5-isoquinolinyl                             1DH    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             3-pyridazinyl                               1DJ    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-thiadiazolyl                              1DK    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             5-tetrazolyl                                1DL    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             2-thiazolinyl                               1DM    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub.3                                                                             3-(1,2,4-triazinyl)                         1DN    CH.sub.3                                                                             CH.sub.3                                                                              CH.sub.3                                                                           CH.sub. 3                                                                            3-(1,2,4-triazolyl)                         ______________________________________                                    

EXAMPLE 2

A mixture of 25 g. (0.09 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile,100 ml. of absolute ethanol and 25 ml. of 35% aqueous sodium hydroxidewas refluxed on a steam bath for seventy hours, and the mixture thendiluted with 250 ml. of water. The oil which separated crystallized oncooling and was collected, washed, and dried to give 17 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 123°-130° C. identical with the compound described above in Example1F.

EXAMPLE 3

To a stirred mixture of 10.5 g. (0.24 mole) of a 57% dispersion ofsodium hydride in mineral oil (which was washed and decanted with hexaneto remove the mineral oil) in 100 ml. of dimethylsulfoxide was added asolution of 29.6 g. (0.1 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidedissolved in 200 ml. of dimethylsulfoxide. The reaction mixture wasstirred for about one and a half hours until evolution of hydrogenceased, and then treated dropwise with 35.5 g. (0.25 mole) of methyliodide. After stirring for an additional two hours, the mixture wasdiluted with about 10 ml. of water, poured onto ice, and the whiteprecipitate was removed by filtration. The filtrate was extracted withether, added to an ether solution of the solid, and the combined organicsolution washed several times with water, dried over sodium sulfate, andevaporated to dryness.

The resulting yellow oil (35.3 g.) was dissolved once again in 200 ml.of dimethylsulfoxide, added to a suspension of 6.0 g. of sodium hydridein dimethylsulfoxide, the mixture warmed to 75° C. for about fiveminutes, treated with 18 g. of methyl iodide as above, and then stirredfor one hour at room temperature. The reaction mixture, when worked upin the manner described above, afforded 31.3 g. of a yellow oil whichslowly crystallized and which was recrystallized from a methanol/watermixture to give 27.7 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-N,N-dimethylcarboxamide,m.p. 100°-104° C.

It is contemplated that by following a procedure similar to thatdescribed in Example 3, using an appropriate 2-R₇-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamideand an appropriate lower-alkyl halide, the following compounds ofFormula I can be prepared where, in each instance, R₃, R₄, R₅ and bothR₆ groups are each CH₃, and X is 0.

                  Table 3                                                         ______________________________________                                        Example    R.sub.1                                                                              R.sub.2    R.sub.7                                          ______________________________________                                        3A         CH.sub.3                                                                             H          CH.sub.3                                         3B         CH.sub.3                                                                             CH.sub.3   CH.sub.3                                         3C         CH.sub.3                                                                             H          CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                  1                                                3D         CH.sub.3                                                                             CH.sub.3   CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                  1                                                3E         CH.sub.3                                                                             H          CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                3F         CH.sub.3                                                                             CH.sub.3   CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                3G         CH.sub.3                                                                             H          C.sub.6 H.sub.5                                  3H         CH.sub.3                                                                             H          2-pyridyl                                        3J         CH.sub.3                                                                             CH.sub.3   2-pyridyl                                        ______________________________________                                    

EXAMPLE 4

A 2.53 g. (0.06 mole) portion of a 57% dispersion of sodium hydride inmineral oil was washed free of mineral oil by slurrying and decantationwith hexane, and was then slurried in 40 ml. of dimethylsulfoxide. Tothe mixture was added a solution of 8.8 g. (0.04 mole) of2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 1A), and the mixture was stirred at roomtemperature for one hour. The mixture was then treated with 8.1 g. (0.06mole) of cyclopropylmethyl bromide, stirred at room temperatureovernight, poured into water, and the mixture extracted with diethylether. The ether extracts, on drying and evaporation to dryness,afforded a brown oil which was chromatographed on silica gel using a 3%isopropanol in ether solution as eluent. There was thus obtained acrystalline material which was slurried with ether/pentane to give 0.55g. of2-cyclopropylmethyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 145°-148° C. identical with that described above in Example 1AL.

EXAMPLE 5

To a solution of 4.45 g. (0.013 mole) of2-phenyl-1-hydroxymethyl-3-carboxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamidein 15 ml. of dimethylformamide was added 0.61 g. (0.014 mole) of a 57%mineral oil dispersion of sodium hydride, the mixture was stirred fortwo hours and then treated with 0.8 g. of methyl iodide and stirred atambient temperature for about twelve hours. The mixture was then pouredinto water, and the solid was collected and recrystallized from acetoneto give 2.3 g. of2-phenyl-1-hydroxymethyl-3-carbomethoxy-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 226°-227° C.

EXAMPLE 6

A solution of 3.05 g. (0.01 mole) of2-[3-(dimethylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 1B) in 30 ml. of isopropanol was treatedwith 2.1 g. of methyl iodide, and the mixture was allowed to stand atroom temperature overnight. The material which had separated was thencollected, washed with isopropanol and pentane and dried to give 4.5 g.of2-[3-(dimethylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidemethiodide, m.p. 128°-130° C. A solution of 10.2 g. (0.06 mole) ofsilver nitrate in 102 ml. of hot water was treated with a solution of2.34 g. of sodium hydroxide in 24 ml. of hot water. The resultingprecipitate was washed five times by decantation with hot water, thenfiltered, and the solid added to a solution of about 9 g. (0.02 mole) of2-[3-(dimethylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidemethiodide in 60 ml. of water. The mixture was stirred at roomtemperature overnight, then filtered, the filter washed first with hotwater and then with ethanol, the aqueous and the ethanol filtrates beingset aside separately for further work. The ethanol washings wererefiltered, evaporated to dryness, and the solid residue which slowlycrystallized was set aside and combined with organic material obtainedby evaporation to dryness of the aqueous filtrate, heating the solidresidue on a steam bath for three hours under a vacuum pump, extractionof the residue with ethyl acetate and evaporation to dryness of theextracts. The combined material obtained from the aqueous and ethanolwashings were recrystallized from ethyl acetate/pentane to give twocrops totaling 0.7 g. of2-allyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 96°-98° C.

EXAMPLE 7

To a suspension of 1.025 g. of2-phenyl-2,4,5,6-tetrahydro-1,3-diformyl-4,6,6,-trimethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 1AB) in 10 ml. of ethanol was added withstirring a suspension of 250 mg. of sodium borohydride in ethanol, andthe resulting clear solution was allowed to stand at room temperaturefor two hours. The white crystalline solid which separated wascollected, washed with water and dried to give 645 mg. of product. Thismaterial was combined with that obtained by evaporation to dryness ofthe filtrate from the main product and trituration with water andcollection and drying of the residual solid. There was thus obtained anadditional 344 mg. of2-phenyl-2,4,5,6-tetrahydro-1,3-bis-hydroxymethyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamideethanolate, m.p. 115°-120° C. The hydrate, m.p. 144°-147° C., wasobtained in another run (12.0 g. from 15.0 g. of starting material) byprecipitation from aqueous ethanol.

Following a procedure similar to that described in Example 7, thefollowing compounds of Formula I were prepared where, in each instance,R₁ and R₂ are each hydrogen and R₃, R₄ and R₅ are each methyl.

                                      Table 7                                     __________________________________________________________________________    Example                                                                            R.sub.6    R.sub.7                                                                             Wt. S.M.                                                                           Wt. Prod.                                                                          m.p.(°C.)/Solvent                      __________________________________________________________________________    7A   CH.sub.2 OH (1)                                                                          C.sub.6 H.sub.5                                                                     2.0  1.59 170-171/ethyl                                      H (3)                      acetate                                       7B   CH.sub.2 OH (1)                                                                          C.sub.6 H.sub.5                                                                     2.3  1.8  184-185                                            CH.sub.3 (3)                                                             7C   CH.sub.2 OH (1)                                                                          4-FC.sub.6 H.sub.4                                                                  3.0  2.0  140-190/ethyl                                      COOH (3)                   acetate                                       7D   CH.sub.2 OH (1)                                                                          C.sub.6 H.sub.5                                                                     6.11 3.37 150-185/ethyl                                      COOH (3)                   acetate                                       7E   CH.sub.2 OH (1)                                                                          4-FC.sub.6 H.sub.4                                                                  2.0  1.3  182-183/benzene                                    H (3)                                                                    7F   H (1)      C.sub.6 H.sub.5                                                                     2.8  2.3  158-159/benzene                                    CH.sub.2 OH (3)                                                          7G   CH.sub.3 (1)                                                                             C.sub.6 H.sub.5                                                                     401  4.2.sup.(a)                                                                        144-147/isopropanol                                CH.sub.2 OCH(CH.sub.3).sub.2 (3)                                         7H   CH.sub.3 (1)                                                                             C.sub.6 H.sub.5                                                                     1.0  0.9  173-179/aqueous                                    CH.sub.2 OH (3)            ethanol                                       7J   CH.sub.2 OH                                                                              C.sub.6 H.sub.5                                                                     6.2  1.0  116.5-118.5/                                                                  ethanol                                       7K   CH.sub.2 OH (1)                                                                          C.sub.6 H.sub.5                                                                     0.9  0.4  220-222.5/                                         CH═CHCOOC.sub.2 H.sub.5 (3)                                                                          acetonitrile                                  7L   CH.sub.2 OH (1)                                                                          C.sub.6 H.sub.5                                                                     2.4  1.7  119-120/ethanol-                                   C.sub.2 H.sub.5 (3)        water                                         7M   CH.sub.3 (1)                                                                             C.sub.3 H.sub.7                                                                     2.0  1.0  130-132/                                           CH.sub.2 OH (3)            acetonitrile                                  7N   CH.sub.2 OH (1)                                                                          C.sub.3 H.sub.7                                                                     3.0  2.6  144-146/ethanol-                                   H (3)                      water                                         7P   CH.sub.2 OH (1)                                                                          4-ClC.sub.6 H.sub.4                                                                 2.0  1.3  212-213/                                           H (3)                      acetonitrile                                  7Q   CH.sub.2 OH (1)                                                                          3-ClC.sub.6 H.sub.4                                                                 2.0  1.0  176-177/CH.sub.2 Cl.sub.2 -                        H (3)                      hexane                                        7R   CH.sub.2 OH (1)                                                                          4-HOC.sub.6 H.sub.4                                                                 1.3       243-249                                            H (3)                                                                    __________________________________________________________________________     .sup.(a) Obtained by recrystallizing 10 g. (of 444 g. obtained) of the        corresponding 3hydroxymethyl compound from isopropanol.                  

EXAMPLE 8

A solution of 10 g. (0.034 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidein 4.5 liters of chloroform was stirred under a high intensity lightwhile bubbling air through the mixture for about sixteen hours. Themixture was then taken to dryness in vacuo and the residue dissolved inbenzene and chromatographed on a column of activated magnesium silicate,the product being eluted first with benzene and then with ether. Thecombined eluates were diluted with ethyl acetate, and the solid whichseparated was collected and dried to give 1.05 g. of material which wasshown by its n.m.r. and mass spectra and by chemical analysis to be2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]-pyrrole-4-carboxamide,m.p. 201°-204° C. (Another sample showed m.p. 207°-209° C.)

In another experiment, a solution of 75 mg. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidein a concentration of 1 mg./ml. in chloroform was exposed to sunlightfor about five days and the solution then evaporated to a concentrationof 10 mg./ml., chromatographed on alumina and eluted with 1:1chloroform-methanol. A total of five bands was developed, the first ofwhich yielded 7.8 mg. and the third 33.3 mg. of material both of whosemass spectra showed a molecular ion of 310 (calculated 308.4) and whosen.m.r. spectrum showed the first to be2-phenyl-1-formyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,identical with the compound described above in Example 1AW, and thethird to be the isomeric2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide.

EXAMPLE 9

2-Phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carbonitrile(8.35 g., 0.03 mole) was combined with 4.6 ml. of 85% hydrazide hydrate,5.25 g. of solid potassium hydroxide and 50 ml. of triethylene glycol,and the mixture was refluxed for one and one half hours under nitrogen.The low boiling components were distilled off until the pot temperaturereached 205° C., and the mixture was then heated an additional two hoursat that temperature. The mixture was cooled, poured into ice water, andextracted with ethyl acetate. The aqueous phase was acidified withconcentrated sulfuric acid, and the solid which separated was collectedand dried to give 6.2 g. of2-phenyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxylicacid.

The latter (6.18 g., 0.22 mole) was dissolved in 70 ml. oftetrahydrofuran, the solution treated with 4.25 g. (0.026 mole) ofN,N'-carbonyldiimidazole, and the solution stirred for six hours at roomtemperature. A solution of 5 ml. of liquid ammonia in 20 ml. oftetrahydrofuran was then added gradually and the solution stirred atroom temperature for about fifteen hours. The solid which separated wascollected and dissolved in ethyl acetate and the solution washed firstwith dilute alkali, then with brine, dried and taken to dryness. Thepale yellow residual solid was recrystallized once from ethyl acetateand once from methanol to give 1 g. of2-phenyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 185°-202° C.

EXAMPLE 10

A solution of 25 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 1F) in 500 ml. of chloroform containing about0.75% ethanol was stirred at ambient temperature for four days whilebubbling air through the solution. The solution was then taken todryness and the residue eluted with diethyl ether/hexane. There was thusobtained material having m.p. 95°-100° C. whose mass spectrum showed amolecular ion of 384 (calculated 384) and which was shown from itsn.m.r. spectrum to be2-phenyl-1,3-diethoxymethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide.

The latter, on reaction with hydrochloric acid in chloroform, afforded amixture which was separated by chromatography into two components, themajor component being2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetra-methylcyclopenta[c]pyrrole-4-carboxamideand the minor being the isomeric2-phenyl-1-formyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamidewhich were shown by their mass and n.m.r. spectra to be identical withthe respective compounds described above in Example 8.

EXAMPLE 11

A solution of 2.0 g. (0.006 mole) of the2-phenyl-2,4,5,6-tetrahydro-1,3-bis-hydroxymethyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamidedescribed in Example 7J in 50 ml. of methanol was treated with 0.11 g.of p-toluene-sulfonic acid, the solution was stirred at room temperaturefor an hour and a half and then taken to dryness. The residue wasdissolved in methylene dichloride, the solution washed with saturatedsodium bicarbonate and brine, then dried over sodium sulfate and takento dryness, and the crude product recrystallized from benzene/hexane togive 2.2 g. of2-phenyl-2,4,5,6-tetrahydro-1,3-bis-methoxymethyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 168°-169.5° C.

EXAMPLE 12

A mixture of 15.0 g. (0.05 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 1F), 15.0 g. (0.38 mole) of sodium hydroxide, 150ml. of ethylene glycol and 1.0 ml. of water was refluxed in a stainlesssteel round bottom flask for two days. The mixture was then cooled,poured into about one liter of water and acidified with glacial aceticacid. The solid which separated was washed with water and recrystallizedfrom methanol to give 8.0 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylicacid, m.p. 131°-136° C.

EXAMPLE 13

A stirred solution of 9.0 g. (0.03 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylicacid (described in Example 12) in 100 ml. of anhydrous tetrahydrofuranwas treated with 5.4 g. (0.033 mole) of N,N'-carbonyldiimidazole and thesolution stirred at ambient temperature for eighteen hours. Theresulting solution was then treated with 3.5 g. (0.04 mole) of2-dimethylaminoethylamine in 50 ml. of tetrahydrofuran, and the mixturestirred for an additional six hours. The solution was then concentratedto dryness in vacuo. The residue was partitioned between 200 ml. ofwater and 100 ml. of ether, and the organic layer was separated, washedwith brine, dried, and taken to dryness to give 10.8 g. of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-{N-[2-(dimethylamino)ethyl]}carboxamideas a clear colorless oil.

It is contemplated that by following a procedure similar to thatdescribed above in Example 13, using the2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylicacid described in Example 12 and an appropriate tertiaryamino-lower-alkylamine, the following compounds of Formula I can beprepared where, in each instance, R₂ is hydrogen; R₃, R₄, R₅ and R₆ areCH₃ ; R₇ is phenyl; and X is 0.

                  Table 13                                                        ______________________________________                                        Example          R.sub.1                                                      ______________________________________                                        13A              CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2 O               13B              CH.sub.2 CH.sub.2 N(CH.sub.2).sub.4                          13C              CH.sub.2 CH.sub.2 N(CH.sub.2).sub.5                          ______________________________________                                    

EXAMPLE 14

A suspension of 15.0 g. (0.05 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylicacid (described in Example 12) and 6.0 g. (0.06 mole) of potassiumbicarbonate in dimethylformamide was stirred at room temperature for twoand one half hours at 60° C. for a half hour, then cooled and treatedwith 14 g. (0.1 mole) of methyl iodide in dimethylformamide and themixture stirred overnight. The resulting dark solution was taken todryness in vacuo, and the dark residual viscous oil was distilled invacuo to give 5.9 g. of methyl2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxylate,b.p. 130°-132° C./0.05 mm.

EXAMPLE 15

A solution of 9.0 g. (0.03 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]-pyrrole-4-carboxylicacid (described in Example 12) in 50 ml. of anhydrous tetrahydrofuran,and the solution treated with 5.4 g. (0.033 mole) ofN,N'-carbonyldiimidazole. The mixture was then treated with a solutionof 2.9 g. (0.03 mole) of aniline in 25 ml. of tetrahydrofuran, thesolution stirred at room temperature for twenty-four hours, and thentaken to dryness in vacuo. The residue was partitioned between water anddiethyl ether, and the ether layer was washed with brine, then dried andtaken to dryness leaving 10.8 g. of a solid residue which wasrecrystallized twice from methanol to give 4.7 g. of1-(2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethycyclopenta[c]pyrrole-4-ylcarbonyl)imidazole, m.p. 134°-136° C.

EXAMPLE 16

A mixture of 29.6 g. (0.1 mole) of2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 1F) and 0.10 g. of cupric acetate monohydrate in300 ml. of 4:6 methanol/benzene mixture was stirred under two atmosperesof oxygen for twenty hours. The resulting black solution was taken todryness, and the residual dark semi-solid was dissolved in 300 ml. ofmethylene dichloride and the solution washed with water, then withsaturated brine, charcoaled, filtered and taken to dryness. The residuewas recrystallized twice from methanol to give 14.1 g. of a mixture of2-phenyl-1-methoxymethyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]-pyrrole-4-carboxamideand2-phenyl-3-methoxymethyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 181°-193° C.

EXAMPLE 17

A mixture of 10 g. (0.032 mole) of2-phenyl-1-formyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]-pyrrole-4-carboxamide(described in Example 8) and 1.0 g. of 10% palladium-on-charcoal in 100ml. of 2-(2-ethoxy)-ethoxyethanol was heated to reflux under nitrogenfor eight hours and then cooled and allowed to stand at ambienttemperature for about twelve hours. The catalyst was removed byfiltration, the filtrate poured into water and the mixture extractedwith benzene. The benzene extracts, after washing, drying andevaporation to dryness, gave a yellow gum which was triturated withether and recrystallized from benzene to give 0.9 g. of2-phenyl-2,4,5,6-tetrahydro-3,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 186°-190° C.

EXAMPLE 18

A solution of 2.96 g. (0.01 mole) of2-phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carboxamide(described in Example 1AV) in 30 ml. of benzene and 120 ml. oftetrahydrofuran was cooled to -5° C. under nitrogen and then treatedwith 5.7 ml. (0.012 mole) of a 2.1 molar solution of diethyl aluminumcyanide in benzene. The mixture was stirred at -5° to -10° C. for twentyminutes, then for one hour at ambient temperature, poured onto 150 g. ofice, acidified with 10 ml. of acetic acid and extracted with benzene.The benzene extracts yielded an amorphous foam which solidified ontrituration with benzene. There was thus obtained 2.75 g. of2-phenyl-1-(hydroxycyanomethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamideas the hemi-benzene solvate, slowly decomposes at 120° C., resolidifiesand melts again at 142° C.

EXAMPLE 19

To a solution of 1.0 g. (0.003 mole) of2-phenyl-1-hydroxymethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 7A) in 7 ml. of pyridine was added 570 mg. (0.004mole) of 4-methylbenzoyl chloride. The reaction mixture was refrigeratedfor two days, poured into saturated sodium bicarbonate solution,extracted with methylene dichloride and the organic extracts dried andevaporated to dryness to give 1.3 g. of residue which was recrystallizedfrom ethyl acetate to give 696 g. of2-phenyl-1-(4-methylbenzoyloxymethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 200°-204° C.

Using the procedure described in Example 19, the following compounds ofFormula I, where in each case R₁, R₂ and R₆ (3-position) are eachhydrogen, R₃, R₄ and R₅ are each CH₃ and R₇ is C₆ H₅, were prepared from2-phenyl-1-hydroxymethyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta-[c]pyrrole-4-carboxamideand acetic anhydride or succinic anhydride.

                                      Table 19                                    __________________________________________________________________________    Example                                                                            R.sub.6 (1) Wt. S.M.                                                                           Wt. Prod.                                                                          m.p.(°C.)/Solvent                           __________________________________________________________________________    19A  CH.sub.2 COOCH.sub.2                                                                      2.0  1.46 174-175/ethyl acetate                              19B  HOOC(CH.sub.2).sub.2 COOCH.sub.2                                                          2.0  0.9  152-154/ethyl acetate-                                                        hexane                                             __________________________________________________________________________

EXAMPLE 20

To a solution of 1 g. (0.0025 mole) of2-phenyl-1-(3-carboxypropionyloxymethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide(described in Example 19B) in 10 ml. of tetrahydrofuran at 0°-5° C. wasadded anhydrous ammonia by passing the gas over the surface of thesolution. The mixture was diluted with ether and the gummy solid whichseparated solidified on scratching to give 1.0 g. of the correspondingammonium salt, m.p. 116°-118° C.

EXAMPLE 21

To a suspension of 2.96 g. (0.01 mole) of2-phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carboxamide(described in Example 1AV) in 50 ml. of tetrahydrofuran was added 12.9ml. of a 0.16 molar solution of methyl lithium while cooling themixture. After stirring for one hour at 0°-5° C. and for two hours atambient temperature, the mixture was poured into ice/aqueous ammoniumchloride and extracted with methylene dichloride. The extracts, ondrying and evaporation to dryness, gave crude product which wasrecrystallized from methylene dichloride-heptane to give 1.91 g. of2-phenyl-1-(1-hydroxyethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carboxamide,m.p. 135°-145° C. consisting of a mixture of the two possible racemicpairs. One of the pure racemates was obtained by recrystallization of 35g. of the di-racemate mixture from aqueous ethanol to give 16 g. of amono-racemate as the ethanolate, m.p. 165°-168° C.

Using a procedure similar to that described in Example 21 above, thefollowing compounds of Formula I, where in each case R₁ and R₂ are eachhydrogen and R₃, R₄ and R₅ are each CH₃ were prepared by reaction of anappropriate organo lithium with an appropriate 1- or3-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide.

                                      Table 21                                    __________________________________________________________________________    Example                                                                            R.sub.6        R.sub.7                                                                            Wt. S.M.                                                                           Wt. Prod.                                                                          m.p.(°C.)/Solvent                   __________________________________________________________________________    21A  CH.sub.3 (1)   C.sub.6 H.sub.5                                                                    3.0  1.09 108-111/ether-                                  CHOHCH.sub.3 (3)              hexane                                     21B  CH.sub.2 ═CHCHOH (1)                                                                     C.sub.6 H.sub.5                                                                    5.92 2.07 144-146/benzene                                 H (3)                                                                    21C  CH.sub.3 (1)   C.sub.6 H.sub.5                                                                    6.0  4.12 151-154/aceto-                                  C.sub.6 H.sub.5 CHOH (3)      nitrile                                    21D  CH.sub.3 (1)   C.sub.6 H.sub.5                                                                    6.0  2.88 160-165/ethyl                                   CH.sub.2 ═CHCHOH (3)      acetate                                    21E  C.sub.4 H.sub.9 CHOH (1)                                                                     C.sub.6 H.sub.5                                                                    5.92 2.4  75-80/-                                         H (3)                                                                    21F  CH.sub.3 (1)   C.sub.6 H.sub.5                                                                    2.0  0.68 184-186/ether-                                  C(CH.sub.3).sub.2 OH (3)      hexane                                     21G  C.sub.2 H.sub.5 CHOH (1)                                                                     C.sub.6 H.sub.5                                                                    2.96 2.62 155-156/ether-                                  H (3)                         heptane                                    21H  CH.tbd.CCHOH (1)                                                                             C.sub.6 H.sub.5                                                                    2.96 1.6  178-179/ether-                                  H (3)                         hexane                                     21J  C.sub.3 H.sub.7 CHOH (1)                                                                     C.sub.6 H.sub.5                                                                    5.82 5.5  139-140/ether-                                  H (3)                         hexane                                     21K  (CH.sub.3).sub.3 COCOCH.sub.2 CHOH (1)                                                       C.sub.6 H.sub.5                                                                    2.96 2.7  142-143/CH.sub.2 Cl.sub.2 -                     H (3)                         heptane                                    21L  CH.sub.2 ═CHCH.sub.2 CHOH (1)                                                            C.sub.6 H.sub.5                                                                    5.82 4.59 108-109/CH.sub.2 Cl.sub.2 -                     H (3)                         hexane                                     21M  C.sub.2 H.sub.5 OCOC.tbd.CCHOH (1)                                                           C.sub.6 H.sub.5                                                                    5.82 4.59 85-87/ether-                                    H (3)                         hexane                                     21N  CH.sub.3 CHOH (1)                                                                            C.sub.3 H.sub.7                                                                    3.78 0.46 149-150/CH.sub.2 Cl.sub.2 -                     H (3)                         heptane                                    21P  C.sub.6 H.sub.5 CHOH (1)                                                                     C.sub.3 H.sub.7                                                                    4.0  1.85 144-146/CH.sub.2 Cl.sub.2                       H (3)                                                                    21Q  4-CH.sub.3 OC.sub.6 H.sub.4 CHOH (1).sup.(a)                                                 C.sub.6 H.sub.5                                                                    5.02 1.73 183-185/aceto-                                  H (3)                         nitrile                                    21R  CH.sub.3 CHOH (1)                                                                            3-ClC.sub.6 H.sub.4                                                                3.30 1.07 142-144/ether-                                  H (3)                         hexane                                     21S  CH.sub.3 CHOH (1)                                                                            4-ClC.sub.6 H.sub.4                                                                2.55 1.2  198-200/CH.sub.2 Cl.sub.2 -                     H (3)                         hexane                                     __________________________________________________________________________     .sup.(a) 4-Methoxyphenyl magnesium bromide used as the organo metallic        reagent.                                                                 

EXAMPLE 22

A solution of 5.82 g. (0.02 mole) of2-phenyl-1-formyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamidein 150 ml. of tetrahydrofuran was cooled to 0°-5° C. and treated withstirring over a period of two hours with 24.4 ml. (0.02 mole) of a 1.8molar solution of propyl magnesium chloride in diethyl ether. Whenaddition was complete, the mixture was allowed to stand for sixteenhours at ambient temperature and then poured onto a mixture of ice andsaturated ammonium chloride solution and the mixture extracted withdiethyl ether. The organic extracts were combined, dried over magnesiumsulfate, and the solvent removed to give a residual solid, which wasrecrystallized from hexane/benzene to give 2.46 g. of2-phenyl-1-[1-(2-butenyl)]-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 156°-157° C.

EXAMPLE 22A

A solution of 3.0 g. of2-phenyl-1-(1-hydroxyethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamidein 150 ml. of benzene was boiled for one hour, then taken to dryness invacuo and the residue recrystallized from ethanol to give 2.2 g. of2-phenyl-1-ethenyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 195°-196° C.

EXAMPLE 23

To 40 ml. of 90% sulfuric acid cooled to 0°-5° C. was added 4.0 g.(0.012 mole) of2-phenyl-1-(hydroxycyanomethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 18), and the mixture was stirred at 0°-5° C.for thirteen hours. The mixture was then poured onto ice, extracted withether, and the ether extracts combined and set aside. Extraction of theaqueous layer with methylene dichloride and isolation of the organicmaterial from the extracts afforded material which was recrystallizedfrom benzene to give 1.0 g. of 2-phenyl1-(aminocarbonylhydroxymethyl)-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamideas the hemi-benzene solvate, m.p. 129°-131° C.

EXAMPLE 24

A solution of 1.2 g. (0.003 mole) of2-phenyl-3-carbethoxyethyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 1BC) in 7.86 ml. of a 1 molar solution ofpotassium hydroxide in methanol containing 5 percent water was stirredat ambient temperature for ten hours and then extracted with ether. Theaqueous layer was then acidified with excess 6 N hydrochloric acid andextracted with ether. The combined ether extracts, on drying andevaporation to dryness, afforded a solid residue which wasrecrystallized from acetonitrile to give 1.0 g. of2-phenyl-3-carboxyethyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 187°-188° C.

EXAMPLE 24A

Proceeding in a manner similar to that described in Example 24 above, asolution of 7.72 g. (0.02 mole) of2-(4-carbethoxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide(described above in Example 1BK) was dissolved in a solution of 40 ml.of ethanol and 40 ml. of water, treated with 0.86 g. of sodium hydroxideand the solution stirred and refluxed on a steam bath for an hour and ahalf. The mixture was worked up in the manner described in Example 24 togive 5.05 g. of2-(4-carboxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide,m.p. 285°-287° C.

EXAMPLE 25

It is contemplated that reaction of an appropriate2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrilein an autoclave at 150°-160° C. with an ethanol solution saturated withanhydrous ammonia and anhydrous hydrogen sulfide would afford thefollowing compounds of Formula I where, in each instance, R₁ and R₂ arehydrogen; R₃, R₄, R₅ and both R₆ groups are each CH₃ ; and X is S.

                  Table 25                                                        ______________________________________                                        Example        R.sub.7                                                        ______________________________________                                        25A            CH.sub.3                                                       25B            CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                   25C            CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                              25D            C.sub.6 H.sub.5                                                25E            2-pyridyl                                                      25F            CH.sub.2 CH.sub.2 CSNH.sub.2                                   ______________________________________                                    

It is contemplated that following the procedures described below, thecompounds described in Examples 26-32 can be prepared.

EXAMPLE 26

Reaction of the ethyl4-carbamoyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-2-acetatedescribed above in Example 1AC with alcoholic sodium hydroxide andisolation of the product from an acid or neutral medium affords4-carbamoyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-2-aceticacid.

EXAMPLE 27

Reaction of the2-(4-carboxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidedescribed above in Example 24A with methanol in the presence of a smallamount of a mineral acid affords2-(4-carbomethoxyphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.

EXAMPLE 28

Reaction of the2-(3-methylmercaptophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidedescribed above in Example 1CK with one molar equivalent of performicacid in acetone at room temperature affords2-(3-methylsulfinylphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.

EXAMPLE 29

Reaction of the2-(3-methylmercaptophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamidedescribed above in Example 1CK with two molar equivalents of performicacid in acetone at room temperature affords2-(3-methylsulfonylphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.

EXAMPLE 30

Reaction of the2-phenyl-2,4,5,6-tetrahydro-1,3-diformyl-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamidedescribed above in Example 1AB with two molar equivalents of perbenzoicacid in acetone at room temperature affords2-phenyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]-pyrrole-4-carboxamido-1,3-dicarboxylicacid.

EXAMPLE 31

Reaction of the2-phenyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamido-1,3-dicarboxylicacid described above in Example 30 with methanol in the presence of asmall amount of a mineral acid affords dimethyl2-phenyl-2,4,5,6-tetrahydro-4,6,6-trimethylcyclopenta[c]pyrrole-4-carboxamido-1,3-dicarboxylate.

EXAMPLE 32

Reaction of1-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrilewith one molar equivalent of diisobutyl aluminum hydride intetrahydrofuran, and, without isolation of the product, oxidation of theresulting material with oxygen affords2-phenyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide.

BIOLOGICAL TEST RESULTS

Data obtained on administration in rats of the compounds of Formula I inthe anti-secretory and the reserpine-induced anti-ulcer tests are givenin terms of the % increase in the pH of gastric fluid over controlanimals and the % reduction in ulcer score over control animals. Dosesare expressed in mg./kg., and unless noted otherwise by the designationi.p., s.c. and i.d. representing intraperitoneal, subcutaneous andintraduodenal, respectively, were obtained on oral administration.Compounds are considered active if any measurable increase in the pH ordecrease in ulcer score over controls are obtained, although forpurposes of further evaluation for possible ultimate commercialdevelopment, compounds were not considered further unless an increase inpH in the anti-secretory test of 80% or a reduction of 30% in the ulcerscore in the anti-ulcer test were obtained. The compounds are identifiedby the Example number above where they are disclosed.

    ______________________________________                                        Example                                                                              Dose    % pH Increase                                                                             % Reduction Ulcer Score                            ______________________________________                                        1      25        9            60                                                     50        50           60                                                     100       84           100                                                    200       96           100                                             1A               Inactive     Inactive                                        1B     100       20           40                                              1C     100       24           Inactive                                        1D     100       7            Inactive                                        1E     100       4            Inactive                                        1F     12.5      41           --                                                     25        52           73                                                     50        75           100                                                    100       100          100                                             1G     25        --           40                                                     50        55           60                                                     100       93           --                                                     100       95           100                                             1H     25        56           60                                                     50        80           100                                                    100       93           100                                             1J     100       4            60                                              1K     25        --           100                                                    50        --           100                                                    100       46           100                                                    200       49           --                                              1L     100       10           Inactive                                        1M     100       16           Inactive                                        1N     100       35           70                                              1P     100       45           100                                             1Q     100       20           80                                              1R     100       16           Inactive                                        1S     100       27           Inactive                                        1T     50        --           80                                                     100       47           90                                              1U     100       9            Inactive                                        1V     25        --           80                                                     50        32           100                                                    100       45           --                                                     100       64           100                                             1W     100       20           20                                              1X     100       5            Inactive                                        1Y     100       145          100                                             1Z     100       77           40                                              1AA    100       26           40                                              1AB    100       18           Inactive                                        1AC    100       4            Inactive                                        1AD    25        3            --                                                     50        11           --                                                     100       16           Inactive                                        1AE    50        157          100                                                    100       253          --                                                     200       400          --                                              1AF    25        --           20                                                     50        20           --                                                     100       21           --                                              1AG    100       Inactive     20                                              1AH    100       Inactive     40                                              1AK    25        48           20                                                     50        110          --                                                     100       120          --                                              1AL    25        33           --                                                     50        75           100                                                    100       325          --                                              1AM    100       14           100                                             1AN    100       54           80                                              1AP    50        8            80                                              1AQ    100       10           20                                              1AR    100       18           Inactive                                        1AS    100       27           100                                             1AT    12.5      236          --                                              1AU    50        --           40                                                     100       68           --                                              1AV    50        --           100                                                    100       38           --                                              1AW    100       38           40                                              1AX    100       Inactive     20                                              1AY    100       Inactive     20                                              1BA    100       Inactive     --                                                     100 i.p.  50           --                                              1BB    100       10           --                                                     100 i.p.  60           --                                              1BC    100       20           --                                                     100 i.p.  20           --                                              1BD    100       10           --                                                     100 i.p.  20           --                                              1BE    100       10           --                                                     100 i.p.  10           --                                              1BF    100       Inactive     --                                                     100 i.p.  20           --                                              1BG    100       10           --                                                     100 i.p.  40           --                                              1BH    100       Inactive     --                                                     200       10           --                                                     100 i.p.  20           --                                              1BJ    200       30           --                                                     100 i.p.  40           --                                              1BK    100       Inactive     --                                                     100 i.p.  118          --                                              1BL    100       9            --                                                     200       18           --                                                     50 s.c.   9            --                                                     50 i.d.   18           --                                              1BM    100       Inactive     --                                                     100 i.p.  155          --                                              1BN    200       10           --                                                     100 s.c.  20           --                                              1BP    200       Inactive     --                                                     100 i.p.  10           --                                              3      100       72           100                                             5      100       15           Inactive                                        7      100       8            60                                              7A     12.5      45           --                                                     25        228          --                                                     50        445          --                                                     100       480          --                                              7B     12.5      Inactive     60                                                     25        8            80                                                     50        163          --                                                     100       399          --                                              7C     100       14           20                                              7D     100       Inactive     60                                              7E     100       42           Inactive                                        7F     25        Inactive     --                                                     50        79           80                                                     100       244          --                                              7G     100       18           --                                              7H     12.5      Inactive     --                                                     25        45           --                                                     50        118          --                                                     100       355          --                                              7K     100       20           --                                                     100 i.p.  60           --                                              7L     50        9            --                                                     100       45           --                                                     200       260          --                                                     25 s.c.   27           --                                                     50 s.c.   36           --                                              7M     100       145          --                                                     200       300          --                                                     100 s.c.  509          --                                              7N     100       18           --                                                     100 i.p.  127          --                                              7P     25        Inactive     --                                                     200       Inactive     --                                                     25 s.c.   Inactive     --                                                     25 i.d.   10           --                                                     100 i.p.  45           --                                              7Q     200       10           --                                                     100 i.p.  30           --                                              7R     50        160          --                                                     100       182          --                                                     200       400          --                                                     100 i.p.  470          --                                                     50 s.c.   210          --                                                     50 i.d.   110          --                                              8      50        Inactive     --                                                     100       --           Inactive                                        9      50        10           100                                                    100       140          --                                              11     100       17           Inactive                                        13     50        --           Inactive                                               100       16           80                                              15     100       Inactive     80                                              16     100       51           75                                              17     50        Inactive     --                                                     100       11           --                                              18     100       188          --                                              19     100       27           40                                              19A    100       73           100                                             19B    100       336          --                                              20     25        --           80                                                     50        128          --                                                     100       166          --                                                     200       530          --                                              21     12.5      31           --                                                     25        289          --                                                     50        565          --                                                     100       580          --                                              21A    100       16           --                                              21B    25        7            --                                                     50        587          --                                                     100       600          --                                              21C    100       8            --                                              21D    100       4            --                                              21E    100       24           --                                              21F    100       14           --                                              21G    25        32           --                                                     50        116          --                                                     100       458          --                                              21H    100       9            --                                                     200       300          --                                              21J    100       64           --                                                     200       182          --                                              21K    200       Inactive     --                                                     100 i.p.  160          --                                              21L    100       73           --                                                     200       210          --                                              21M    100       9            --                                                     100 i.p.  9            --                                                     50 i.d.   64           --                                              21N    100       36           --                                              21P    100       Inactive     --                                                     100 i.p.  70           --                                              21Q    100       Inactive     --                                                     100 i.p.  10           --                                              21R    200       10           --                                                     100 i.p.  20           --                                              21S    200       Inactive     --                                                     100 i.p.  9            --                                              22     100       Inactive     --                                                     100 i.p.  27           --                                              22A    100       10           --                                                     100 i.p.  60           --                                              23     100       10           --                                                     100 i.p.  20           --                                              24     100       10           --                                                     100 i.p.  110          --                                              24A    100       10           --                                                     100 i.p.  20           --                                              ______________________________________                                    

Although the species of Examples 1A and 8 were found inactive in boththe anti-secretory and anti-ulcer tests, they are nevertheless useful asintermediates for preparing compounds which are useful as anti-secretoryand/or anti-ulcer agents, the species of Example 1A being used toprepare the species of Example 4 (identical with the species of Example1AL), and the species of Example 8 being used to prepare the species ofExample 7H.

We claim:
 1. A compound having the formula ##STR13## where X is O or S;R₁ and R₂ are each hydrogen or loweralkyl; each of R₃, R₄ and R₅ ishydrogen or methyl; each R₆ group is the same or different hydrogen,phenyl-lower-alkyl, methyl or lower-alkenyl; and R₇ is 2-, 3- or4-pyridyl, and wherein the phenyl-lower-alkyl group can be furthersubstituted in the phenyl nucleus by a single methylenedioxy orloweralkoxy group or by from one to three, the same or different,members of the group consisting of lower-alkyl, halogen, hydroxy,trifluoromethyl, lower-alkanoylamino, amino, di-lower-alkylamino,di-lower-alkylaminomethyl, carboxy, carboxamido, carbo-lower-alkoxy,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, nitro andsulfamoyl except that both R₆ groups are not simultaneously hydrogen. 2.A compound having the formula ##STR14## where R₁ and R₂ are eachhydrogen or lower alkyl; each R₆ group is the same or differenthydrogen, methyl or lower-alkenyl; and R₇ is 2- or 4-pyridyl except thatboth R₆ groups are not simultaneously hydrogen.
 3. A compound accordingto claim 2 where each of R₁ and R₂ is hydrogen; and both R₆ groups aresimultaneously methyl. 4.2-(2-Pyridyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamideaccording to claim
 3. 5.2-(4-Pyridyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamideaccording to claim 3.